Use of Newer Type 2 Diabetes Drugs Gives Hope but Costs a Concern

There is a trend toward greater use of newer glucose-lowering drugs with cardiovascular benefit, raising hopes for better outcomes in patients with type 2 diabetes but with concern about the high cost of the agents, researchers say.

Two new studies explore this relatively recent diabetes prescribing trend.

In one study, use of newer noninsulin glucose-lowering agents with cardiovascular and renal benefits started to increase after 2014, and at the same time, the use of older human insulins was almost entirely replaced with newer high-cost analogs. This study was a cross-sectional analysis of the 2003-2018 US National Health and Nutrition Examination Survey (NHANES).

The other study, of nearly 15,000 patients with type 2 diabetes in 37 countries, found that use of newer agents, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, has risen but remains suboptimal among individuals who could benefit from them the most.

"It's Complicated"

Taken together, the data "underscore the challenges that we face when trying to manage diabetes not just as a disease of hyperglycemia but as a disease of hyperglycemia and increased micro- and macrovascular complications," Rozalina G. McCoy, MD, associate professor of medicine at the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News.

"If we think about diabetes simply as a condition where we have to lower blood glucose levels then it makes sense that we would use the cheapest option available," she added.

"But it's much more complicated than that, and it's not just about lowering blood sugar. It's about reducing cardiovascular events, reducing the progression of kidney disease, and preventing death. The only two medication classes that have been proven to do that in type 2 diabetes are GLP-1 agonists and SGLT2 inhibitors, and they are high-cost medications," she said.

McCoy was not involved in either study but has conducted similar research.

Generics are coming online but aren't yet widely available. But even once they are — and this will need to include them being placed on formularies [in some countries, such as the United States] — they still will be only part of the solution, McCoy believes.

"Just like with insulin, I think generics are part of the solution, but so is lowering the cost of brand-name drugs...We definitely don't want patients to bear the financial burden of their diabetes management, but that shouldn't come at the cost of not giving them evidence-based therapies that will improve their health. We really need to lower the cost of these drugs to make them affordable and accessible to patients and to the healthcare system," she said.

Human Insulin Can Be SafelyUsed in Type 2 Diabetes

The NHANES study, recently published in the Journal of General Internal Medicine by Phuc Le, PhD, of Cleveland Clinic Community Care, Ohio, and colleagues, included 7394 representative US patients with type 2 diabetes.

Their use of low-cost noninsulin drugs (those with at least one generic available) increased from 37% in 2003-2004 to 54% in 2013-2014 (P < .001) and stabilized thereafter.

For high-cost non-insulin drugs (all others), use declined from 2003-2004 to 2013-2014, then slowly increased to 2017-2018, although not significantly (P = .247). Use of metformin and dipeptidyl peptidase 4 (DPP-4) inhibitors increased from 2003-2004 to 2017-2018, while use of sulfonylureas and thiazolidinediones dropped significantly. Use of other noninsulin glucose-lowering drugs was low during the study periods.

However, Le and colleagues note, "with the ADA's latest recommendations to use GLP-1 agonists and SGLT2 inhibitors for patients with cardiovascular disease, heart failure, and chronic kidney disease, the overall use of high-cost noninsulin drugs will likely continue to increase for the foreseeable future, as they will not become generic for at least 10-15 years."

In contrast, use of low-cost human insulin declined from 7% in 2003-2004 to 2% in 2017-2018 (P < .001), while use of high-cost analog insulin rose from 4% to 16% during the same time period.

Le and colleagues say this finding is "of concern" because of the rapid rise in the cost of analog insulin over the past two decades.

"Human insulin, which is 90% less expensive than analogs yet equally effective in glucose control for type 2 diabetes, saw a precipitous decline in use throughout the study period. Use of insulin analogs, promoted by their manufacturers as safer and more convenient, quadrupled in frequency. This trend looks set to continue in future years, as younger generations of physicians lack training on how to prescribe human insulin," the authors write.

McCoy echoed that concern, noting: "We can use human insulin in type 2 but it has to be dosed correctly and match the patient's life...They're used very differently than analogs."

Specifically, McCoy said that for some patients with type 2 diabetes who only require basal insulin and who have regular routines, a single bedtime dose of NPH, an intermediate-acting human insulin, can be effective.

Importantly, she cautioned clinicians against "demonizing" the older human insulins to patients because if they're having financial difficulty they might just purchase them from Walmart without telling their clinician and use them the way the analog had been prescribed without realizing there's a difference.

"That's very dangerous. I want us as clinicians to be comfortable using human insulins so that when we have to use them we can do so effectively and safely," she said.

But at the same time, McCoy stressed, "we need to make analog insulin more affordable."

Use of the high-cost drugs was significantly higher for non-Hispanic Whites than for other racial and ethnic groups, while use of low-cost drugs didn't differ by race/ethnicity. Individuals with health insurance were twice as likely to use high-cost drugs compared to those without health insurance.

Globally, Use of Newer Drugs Rising but Still Suboptimal

The global study was recently published online in BMC Endocrine Disorders by Suzanne V. Arnold, MD, of Saint Luke's Mid America Heart Institute, Kansas City, Missouri, and colleagues. It was part of DISCOVER, a prospective, observational study of 14,575 people with type 2 diabetes starting second-line therapy from 37 countries in Africa, the Americas, Europe, the Middle East, Southeast Asia, and Western Pacific.

At enrollment in 2014-2016, 8.7% of participants were started on an SGLT2 inhibitor, 2.1% on a GLP-1 agonist, and 0.1% on both, increasing within 3 years to 12.8%, 2.6%, and 0.7%, respectively.

Factors increasing the likelihood of being on an SGLT2 inhibitor or GLP-1 agonist included the presence versus absence of coronary artery disease (20.0% vs 13.8%), heart failure (22.5% vs 14.1%), and chronic kidney disease (17.1% vs 14.4%) (all P < .001). In contrast, use was similar for those with versus without cerebrovascular disease (14.7% vs 14.5%; P = .18) and peripheral arterial disease (14.9% versus 14.5%; P = .11).

Median use of both classes was 19% across countries but varied by region, with notably low rates in Africa and Asia and a trend toward higher use in wealthier countries. Countries with particularly high rates of use included Kuwait, United Arab Emirates, Costa Rica, and Norway. (Neither the United States nor United Kingdom was included in this study.)

Use of SGLT2 inhibitors and GLP-1 agonists was 10.4% among patients with type 2 diabetes treated by primary care physicians, 16.9% for endocrinologists, 26.1% for cardiologists, and 22.0% for other specialists.

Greater use of both classes was significantly associated with younger age (odds ratio [OR], 0.77 per 10-year increase), male sex (OR, 1.17), and higher body mass index (OR, 1.51 per 5 kg/m²).

SGLT2 Inhibitors and GLP-1 Agonists Not on WHO List

McCoy noted that, as of now, neither SGLT2 inhibitors nor GLP-1 agonists are included on the World Health Organization's essential medicines list, which dictates availability for low- and middle-income countries.

"I would like to see the day when sulfonylureas are off the list and SGLT2 inhibitors are on...Currently, they're used in wealthier countries by wealthier people who get to see specialists," said McCoy.

But, she noted, "at least in other countries those with comorbidities are more likely to get them, unlike in the United States. Here, it's more about access than indication."

The DISCOVER study program is funded by AstraZeneca. McCoy has reported being a consultant to Emmi on developing diabetes and prediabetes patient education materials. Le and Arnold have reported no relevant financial relationships.

J Gen Intern Med. Published online April 28, 2022. Abstract

BMC Endocr Disord. Published online April 26, 2022. Full text

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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